Nitrophenyl acylamino acyloxy ketones



Patented July 18, 1950 NITROPHENYL AOYLAMINO ACYLOXY KETONES Loren M. Long, Grosse Pointe Woods, Mich., as-

signor to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing. Application July 25, 1949, 1 Serial No. 108,732

5 Claims.

This application is a continuation-in-part of my copending applications Serial No. 45,976, filed August 24, 1948, now abandoned, and Ser. No. 60,182, filed November 15, 1948, and the invention relates to ketonic compounds and to methods for obtaining the same. More particularly, the invention relates to acylamidoacyloxy ketones having the general formula,

is o NH-Acyl @li-on-omon where R1 and R2 have the same significance as given above. Amino hydroxy ketone compounds or. their acid addition salts can also be used as the starting materials in the practice of the invention but the preferred starting materials are the acylamido hydroxy ketones. The amino hydroxy ketones which may also be employed have the following formula in their free base form:

where R1 and R are the same asset forth above.

The acylation of the acylamido hydroxy ketones is carried out by treating the starting material with an acyl halide or acyl anhydride under substantially anhydrous conditions either alone or in the presence of an acylation catalyst such as an inorganic base, an alkaline salt of an organic acid, a tertiary organic base, an aromatic sulfonic acid or sulfuric acid. The acylation can, in general, be carried out at a temperature varying from about -140" C. but the preferred temperature for the reaction is between about 60-l20 C. An inert organic solvent such as benzene, petroleum ether, toluene and the like can be used for the reaction, if desired, although in most cases it is more expedient to omit the use of a solvent and to merely use an excess of the acylating agent. Some of the catalysts which can be used to bring about the reaction in a shorter period of time are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate, pyridine, quinoline, triethylamine, N- ethyl morpholine, N-ethyl piperidine, N,N-dimethyl aniline, p-toluene sulfonic acid and sulfurlc acid.

When the amino hydroxy ketones are used as the starting products, the acylation is carried out in the same manner. If the starting material is employed in the form of one of its acid addition salts, it is preferable to carry out the reaction in the presence of an alkaline catalyst or to atleast partially neutralize the salt by the addition of a weakly alkaline material such as an alkali metal salt of the acid corresponding to the acylating agent.

The products of the invention are particularly useful in. the synthesis of organic compounds possessing antibiotic activity. For example, the pnitrophenyl products of Example 1, 2 and 3 can be converted to the corresponding [d1] l/-1-pnitrophenyl-2-acylamldopropane-1,3-diol compounds by reduction with aluminum isopropylate and these products converted by hydrolysis, resolution and acylation with a dichloroacetic acid to [d1]-r!/-1-p-nitrophenyl-2-dich1oroacetamidopropane-1,3 diol, a product possessing outstanding and unique antibiotic activity. The methods used in these transformations are described more fully and claimed in the following copending applications of ,Harry M. Crooks et al.: Ser. No. 15,264, filed'March 16, 1948, now Patent No. 2,483,884, issued October 4, 1949; Ser. No. 76,179,

filed February 12, 1949, now Patent No. 2,483,885,

issued October 4, 1949; Ser. No. 76,180, filed February 12, 1949.

The invention is illustrated by the following examples.

Y Example 1 [a] 71 g. of p-nitro-w-bromoacetophenone dissolved in 300 cc. of chloroform is added to a solu- 35 agitate 2,615,241 3 4 tie chloroform and dried. The formula of this propiophenone is collected, dissolved in hot alcoproduct is: hol and the solution diluted with warm water. The crystalline product which separates upon LJJHKCMNB, goollug is collected and dried; M. P. 126-30 c. i i m o an ,eetystallizatiomz:fronr iithjilhdcetateuriigises the 32 v it? i M 1:. ced .2 to The p-niim-w-bromoacetophenohehexan'ieth at!) 39 be ylene tetranl ine complex prepared above is mixed Example 2 with a. cold solution of 500 cc. of absolute etnonti and 100 cc. of concentrated hydiggglggriq acid and 1;; ig p;nitro-d-dichloroacetamido-fi-hythe mixture stirred overnight at room temper; fiw p opi p e one is mixed with 9 cc. of acetic ture. The solid roduct which nsists Q1. th hy d ide angj drops of concentrated sulfuric hydrochloride salt of p-niti" ff 5 xture. The reaction mixture none contaminated with ni'i'noralmdiiiits i'fi siia or a few minutes and then hydrobromide salt and ammonium chloride i stirred until the cess lected, Washed with 200 cc. ordcezfooid wate c'et ci. .ohxdridesis hydro y e e solid prodremove the ammonium chloride and dried formula of this compound is:

r. 6; fzthez'p nitroaminoacetophenonezehy drochloride prepared: above is: mixed-with 200 cc. oi-v :acetic-= anhydride lands-; g. 01:sodium.aceta e- 3; The" mixture aid stirred at room temperature and 25 small quantities of ice andwater--aaddedr. from time to time. Stirring is continued until the mixv a u H ture becomes clear and reaches a. temperature of 3 a, about 70 C. The solution is diluted with 900 cc. 15.2 g. of p-nitro-d-benaamido-s-hfid f W 0001811 1 d the ppiophenone is heated ataboutlfimcxifor one hour mi ce ph o l e 153461 with 20 g. of benzoic anhydride and-0.3::cc. of conpit cet doac tophe o e s the centrated sulfuric acid. The reaction mixture is mula. treated with 200 cc. of cold water and the solu- 0 0 tion made alkaline with an excess of 10% sodium NoOg-omN- -cn, hydroxide solution- After standing about onehalf to three quarters of an hour the crystalline 11.1 g. of p-nitro-w-acetamidoacetophenone is p-nitro-a-benzamido-fl-benzoxypropiophenone is mixed with cc. of methanol and 17 cc. of 36- collected, washed with water and purified by 38% aqueous formaldehyde. 0.4 g. of sodium birecrystallization from ethanol.v This product carbonate is added and the mixture stirred at 0 which has the formula, 35 C. for about one hour and a half during which O time the solid product separates. The mixture is i I J LO cooled and stirred for one-half hour, the solid product collected, washed with water and dried at C. The product thus obtained is p-nitro-u- 45 E l acetamido-,8-hydroxypropriophenone, M. P. 166- 0 0 7 C., which has the formula,

Y o is a white, crystalline solid insoluble in water but 0 JL soluble in hot alcohol.

NOPQJ J-dH-OEOH 5o Emample4 i l mixture consisting of 10 g. of o-methyl-p- [b] 8 of p mtro-a'acetamido-fi-hydroxy' nitro-a-ac'etamido B hydroxypropiophenone propiophenone is heated at about C. for onehalf hour with 20 cc. of acetic anhydride contain-.- and 20 i of be-nmlc anhydride heated at r ing a small amount of concentrated sulfuric acid. for abou one-half to three'quafrters of an hour The mixture is cooled, treated with 75 cc. of water The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from methanol or ethanol. The product thus obtained is p-nitro-uacetamido-fi-acetoxypropiophenone which has the formula,

and an excess of cold sodium hydroxide solution added. After standing for a few minutes the precipitate is collected, washed well with water 60 and purified by recrystallization from methanol or ethanol. The product thus produced is 0- methyl p nitro-a acetamido p benzoxyproio henone formula, Nn- -om p p 7 a I 5 Nogilmmim 0 0, ,i v [c] 25.2 g. of p-n itro-a-acetamido p-hydroxy N0 nc niopropiophenone is mixed with cc. of acetic an- I i I I hydride and 0.5 cc. of concentrated sulfuric'acidJ H2 l it I V The mixture is heated at about 50 Cgon astealn I bath untila clear solution is'obtained." After f t c standing overnight the solution is concentrated to v A mixture consisting of 8.8 g. of m methoxy.p-

dryness'in vacuo and the residue mixed with we nitro a :"p' 'toluylamido -fi hydroxypropio ter. The solid p-nitro-d-acetamido-p-acetoxy- 75 phenone, 6 g. of succinic anhydride and 2 drops of concentrated sulfuric acid is heated at C. for about one hour. 150 cc. of cold water is added to the reaction mixture and the insoluble product is collected. The insoluble product is suspended in 100 cc. of cold water and the solution made alkaline to pH 10 by the addition of 10 N sodium hydroxide solution. The solution is extracted with ethyl acetate, the aqueous phase decolorized with charcoal and the clarified solution acidified with dilute hydrochloric acid. The insoluble product which consists of m-methoxyp nitro a p toluylamido fl (p' carboXY- propionyloxy) -propiophenone is collected, washed with water and purified by recrystallization from ethanol. The formula for this white crystalline product is, v

0 1| Til-COCK:

Q o o Example 6 9 g. of 2-nitro-4,5-dimethyl-c-phenacetamidop-hydroxypropiophenone is heated with 10 a. of phenylacetic anhydride and 0.1 cc. of concentrated sulfuric acid with stirring at 80 Cdor one hour. The reaction mixture is treated with 200 cc. oi cold water, made alkaline to pH 10 with 10 N sodium hydroxide solution and allowed to stand for one hour. The insoluble product is collected, washed well with water and purified by recrystallization from ethanol. The white, crystalline water-insoluble product thus obtained is 2- nitro 4,5 dimethyl a phenacetamido flphenacetoxypropiophenone of formula,

Example 7 8 s. of 3-nitro-fi-chloro-a- ('-chloropropionamido) p hydroxypropiophenone is mixed with 8 g. of dry pyridine and the mixture cooled to 0 C. g. of chloroacetyl chloride is added dropwise with stirring. keeping the temperature at about 0 0. After the addition has been completed the mixture is stirred for one-half hour and then treated with 150 cc. of ice water. The insoluble product is collected, washed well with water and purified by recrystallization from ethanol or methanol. The white, crystalline compound thus obtained is 3-nitro-5 chloro a- (c' chloropropionamido) s chloroacetoxypropiophenone oi formula,

' The s-acylamido B hydroxypropiophenones and the corresponding s-amim-pyd omroused as starting materials in the auaau practice oi the invention may be prepared as described in my-copending applications Ser. No. 60,182, filed November 15, 1948, and Serial No. 106,731, filed under even date with the instant application. The process described and claimed I v in said application Ser. No. 60,182 for the preparation of the a-acylamido-p-hydroxypropiophe- Example 1 (a) nones involves reacting 9. nitro substituted 0- acylamidoacetophenone with formaldehyde in the presence of an alkaline condensation catalyst. A specific example of the preparation 01' one of the products used as a starting material, p-nitro-aacetamido-p-hydroxypropiophenone, is given in The process described in said application Serial No. 106,731 for the'preparation of the a-amino-p-hydroxypropiophenone starting materials involves hydrolysis of the corresponding a acylamido-p-hydroxypropiophenone compound. The hydrolysis is preferably carried out using aqueous mineral acid. A specific example of the preparation of one of the starting materials is as follows:

50.4 g. of p-nitro-a-acetamido-p-hydroxypropiophenone in 500 cc. of 18% hydrochloric acid is heated on a steam bath for forty-five minutes and then the solution concentrated to dryness in vacuo after extraction of the solution with ethyl acetate. The solid residue which consists oi. 1)- nitro a-amino-p-hydroxypropiophenone hydrochloride is ground with a little absolute ethanol. collected and washed with absolute ethanol: M. P. 182 C. dec. Recrystallization from hot absolute ethanol (1 g. per cc.) raises the M. P. to 182- 183 C.

What I claim is:

l. A compound of the formula where R1 and R: are members of the class consisting 01' hydrogen, halogen, lower alkyl and lower alkoxy radicals and acyl is a carboxylic acid acyl radical.

2. A compound of the formula 0 NH-Acyl where acyl is a carboxylic acid acyl radical.

3. A compound oi the formula 0 Nn- -om 0 e o No -OJ n-omo -om 4. Acompoundoi the formula O Nn-a-c HO]:

' NOGE-LE-OHgOE-CHQ 5. A compound oithe formula 

1. A COMPOUND OF THE FORMULA 